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Thu October 4, 2012

Ketamine Relieves Depression By Restoring Brain Connections

Originally published on Thu October 4, 2012 5:12 pm

Scientists say they have figured out how an experimental drug called ketamine is able to relieve major depression in hours instead of weeks.

Researchers from Yale and the National Institute of Mental Health say ketamine seems to cause a burst of new connections to form between nerve cells in parts of the brain involved in emotion and mood.

The discovery, described in Science, should speed development of the first truly new depression drugs since the 1970s, the researchers say.

"It's exciting," says Ron Duman, a a psychiatarist and neurobiologist at Yale University. "The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression."

Ketamine is an FDA-approved anesthetic. It's also a popular club drug that can produce out-of-body experiences. Not exactly the resume you'd expect for a depression drug.

But a few years ago, researchers discovered that ketamine could help people with major depression who hadn't responded to other treatments. What's more, the relief came almost instantly.

The discovery "represents maybe one of the biggest findings in the field over the last 50 years," Duman says.

Depression is associated with a loss of so-called synaptic connections between nerve cells, Duman says. So he and other scientists began to study mice exposed to stresses that produce symptoms a lot like those of human depression.

The stressed mice lost connections in certain parts of the brain. But a dose of ketamine was able to "rapidly increase these connections and also to rapidly reverse the deficits that are caused by stress," Duman says.

A team at the National Institute of Mental Health also has found evidence that ketamine works by encouraging synaptic connections.

It's possible to see the change just by studying rodent brain cells with a microscope, says Carlos Zarate from the Mood and Anxiety Disorders Program at NIMH.

A healthy neuron looks like a tree in spring, he says, with lots of branches and leaves extending toward synaptic connections with other neurons. "What happens in depression is there's a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring."

And there's also indirect evidence that ketamine is restoring synaptic connections in people, Zarate says.

His team studied 30 depressed patients who got ketamine. And they found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.

All of this research is intended to produce drugs that will work like ketamine, but without the hallucinations. And several of these alternative drugs are already being tried in people.

Preliminary results suggest that "some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine," Zarate says.

One of these drugs, called GLYX-13, has already been tested in two large groups of people — a key step toward FDA approval. The company that makes the drug, Naurex, says it will tell scientists how well GLYX-13 works at a meeting in December.

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Transcript

MELISSA BLOCK, HOST:

Scientists think they have figured out how an experimental drug called ketamine is able to relieve severe depression within hours instead of weeks.

NPR's Jon Hamilton reports the discovery should speed development of the first truly new depression drugs since the 1970s.

JON HAMIILTON, BYLINE: Ketamine is an FDA-approved anesthetic. It's also a popular club drug that can produce out-of-body experiences. Not exactly the resume you'd expect for a depression drug. But a few years ago, researchers discovered that ketamine could help people with major depression who hadn't responded to other treatments. What's more, the relief came almost instantly.

Ron Duman, a psychiatrist and neurobiologist at Yale University, says the news was a very big deal.

RON DUMAN: When you think about ketamine and its ability to produce a rapid antidepressant response, it represents maybe one of the biggest findings in the field over the last 50 years.

HAMIILTON: So, Duman has been trying to figure out how ketamine is able to work so quickly when other depression drugs take weeks or months. Now he thinks he knows and he lays out his hypothesis in this week's issue of the journal Science. Duman says it has to do with synapses, the connections between nerve cells or neurons.

DUMAN: Depression is associated with an atrophy and loss of synaptic connections. So you actually have an atrophy of neurons and a loss of these important connections that are playing a role in maintaining normal mood and emotion.

HAMIILTON: Duman wanted to know if ketamine was somehow restoring those lost connections, so he studied mice exposed to stresses that produce symptoms a lot like those of human depression. Duman says the stressed mice lost connections in certain parts of the brain, until they got ketamine.

DUMAN: Ketamine is able rapidly increase these connections and also to rapidly reverse the deficits that are caused by stress.

HAMIILTON: Another scientist studying how ketamine works is Carlos Zarate at the National Institute of Mental Health. He says depression not only weakens connections between neurons, it affects the neurons themselves.

CARLOS ZARATE: A healthy neuron will look like a tree in spring. You have branches, you have leaves.

HAMIILTON: Zarate says the leaves are synapses.

ZARATE: What happens in depression, there's a shriveling of these branches and these leaves and it looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring.

HAMIILTON: Zarate says the change is obvious and almost immediate. And it's not just in mice. Zarate was part of a team that studied 30 depressed patients who got ketamine. The researchers found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.

All of this research is intended to produce drugs that work like ketamine without the hallucinations. Zarate says several of these alternatives are already being tried in people.

ZARATE: There are a number of studies that are taking place and are certain preliminary results which suggest that some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine.

HAMIILTON: One of these drugs, called GLYX-13, has already been tested in two large groups of people; a key step toward FDA approval. The company that makes the drug says it will tell scientists how well GLYX-13 works at a meeting in December.

Ron Duman, at Yale, says he's less concerned with the results of any one drug trial than with the prospect of a new generation of depression drugs that work in a totally new way.

DUMAN: The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed, that will ultimately provide a much better way of treating depression.

HAMIILTON: Duman says it's about time. The last truly new drug for depression was Prozac, which was approved in 1987.

Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.

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